Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. The cost of AD is enormous (in the U.S., greater than $100 billion annually) and includes the suffering of the patients, the suffering of families, and the lost productivity of patients and caregivers. As the longevity of society increases, the occurrence of AD will markedly increase. It is estimated that more than 10 million Americans will suffer from AD by the year 2020, if methods for prevention and treatment are not found. Currently, AD is estimated to afflict 10% of the population over age 65 and up to 50% of those over the age of 85. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review see Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373–403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in affected individuals reveals the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome). Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies have shown that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies reveal that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein is designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to its deposition in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Compelling evidence accumulated during the last decade reveals that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β-amyloid precursor protein (APP). (Selkoe 2001; Wolfe 2001)). βAPP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Several proteolytic fragments of APP are generated by proteinases referred to as secretases. A subset of these proteolytic fragments, designated β-amyloid peptide (Aβ), contains 39 to 43 amino acids and is generated by the combined action of β-secretase and γ-secretase. β-secretase is a membrane-bound, aspartyl protease that forms the N-terminus of the Aβ peptide. The C-terminus of the Aβ peptide is formed by γ-secretase, an apparently oligomeric complex that includes presenilin-1 and/or presenilin-2. Presenilin-1 and presenilin-2 are polytopic membrane-spanning proteins that may contain the catalytic components of γ-secretase (Seiffert, Bradley, et al. 2000).
Multiple lines of evidence together strongly suggest that a reduction in brain Aβ levels will prevent the onset and progression of AD. First, Aβ is a major constituent of the parenchemyal plaques observed in all AD patients and the cerebral vasculature amyloid deposits observed in 90% AD patients (reviewed in (Selkoe 2001; Wolfe 2001)). These plaques are formed from the aggregation of soluble Aβ whose brain levels are highly correlated with the severity of AD neurodegeneration (McLean, Cherny et al. 1999). Second, mutations in three genes (APP, PS-1, or PS-2) that increase Aβ cause familial AD (FAD), where AD onset is accelerated by at least a decade. Included in the mutations that increase Aβ are chromosome 21 Trisomy that causes Down's syndrome. Third, transgenic mice that express one or more of the mutant FAD genes have increased Aβ levels, form parenchymal plaques and cerebral vascular deposits containing Aβ, exhibit memory deficits (Chapman, White et al. 1999), and enhance neurofibrillary degeneration in mice that also overexpress mutant tau (Lewis, Dickson et al. 2001). Fourth, Aβ is toxic to cultured cells (Dahlgren, Manelli et al. 2002), induces neurofibrillary tangles in mice with mutant tau (Gotz, Chen et al. 2001), and interferes with long-term potentiation, a likely component of memory ((Walsh, Klyubin et al. 2002) and references therein). Taken together, these data lead one skilled in the art to conclude that excess Aβ production and/or reduced Aβ clearance cause AD. From this it follows that reducing brain Aβ levels by inhibition of γ-secretase will prevent the onset and progression of AD.
In addition to AD, excess production and/or reduced clearance of Aβ causes cerebral amyloid angiopathy (CAA) (reviewed in (Thal, Gherbremedhin et al. 2002)). In these patients, vascular amyloid deposits cause degeneration of vessel walls and aneurysms that may be responsible for 10–15% hemorrhagic strokes in elderly patients. As in AD, mutations in the gene encoding Aβ lead to an early onset form of CAA, referred to as cerebral hemorrhage with amyloidosis of the Dutch type, and mice expressing this mutant protein develop CAA that is similar to patients.
It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment would therefore be based on drugs that inhibit the formation of Aβ in vivo.
Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit β- or γ-secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target γ-secretases, could control the production of Aβ. Such inhibition of β- or γ-secretases could thereby reduce production of Aβ, which, could reduce or prevent the neurological disorders associated with Aβ protein.
As evidenced by the interest in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and Down's Syndrome, a wide variety of compounds which inhibit Aβ protein production have been studied. Copending, commonly assigned PCT international patent applications WO 00/07995 (published Feb. 17, 2000) and WO 00/38618 (published Jul. 6, 2000), disclose lactams of general formula: wherein the lactam ring B is substituted by a substituted succinamido group. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby, acting to prevent or treat the neuropathology associated with production of Aβ-peptide.
Copending, commonly assigned PCT international patent application WO 01/92235, published Dec. 6, 2001, discloses lactams of general formula: wherein the lactam ring B is substituted by cyclic succinamides. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby, acting to prevent or treat the neuropathology associated with production of Aβ-peptide.
Copending, commonly assigned PCT international patent application WO 01/77086, published Oct. 18, 2001, discloses lactams of general formula: as inhibitors of β-amyloid peptide release and having utility in treating Alzheimer's disease. Though some of the present compounds of this invention appear to fall within the generic description of the above publication, they are not specifically disclosed, suggested, or claimed therein.
Thus, it is desirable to develop additional and/or improved inhibitors of Aβ protein production to treat Alzheimer's disease. The present invention discloses compounds of enhanced activity in inhibiting Aβ protein production. None of the above references expressly teach or suggest the compounds of the present invention which are described in detail below.